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Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination of the potential role of primary and secondary HCV resistance in the outcome of treatment
Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803...
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| Published in: | Antiviral therapy 2004-12, Vol.9 (6), p.953-968 |
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| container_title | Antiviral therapy |
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| creator | SOLER, Muriel MCHUTCHISON, John G KWOH, T. Jesse DORR, F. Andrew PAWLOTSKY, Jean-Michel |
| description | Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor ( |
| doi_str_mv | 10.1177/135965350400900612 |
| format | article |
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Jesse ; DORR, F. Andrew ; PAWLOTSKY, Jean-Michel</creator><creatorcontrib>SOLER, Muriel ; MCHUTCHISON, John G ; KWOH, T. Jesse ; DORR, F. Andrew ; PAWLOTSKY, Jean-Michel</creatorcontrib><description>Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.</description><identifier>ISSN: 1359-6535</identifier><identifier>EISSN: 2040-2058</identifier><identifier>DOI: 10.1177/135965350400900612</identifier><identifier>PMID: 15651754</identifier><language>eng</language><publisher>London: International Medical Press</publisher><subject>5' Untranslated Regions - genetics ; Antibiotics. Antiinfectious agents. 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Jesse</creatorcontrib><creatorcontrib>DORR, F. Andrew</creatorcontrib><creatorcontrib>PAWLOTSKY, Jean-Michel</creatorcontrib><title>Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination of the potential role of primary and secondary HCV resistance in the outcome of treatment</title><title>Antiviral therapy</title><addtitle>Antivir Ther</addtitle><description>Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.</description><subject>5' Untranslated Regions - genetics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Drug Resistance, Viral</subject><subject>Evolution, Molecular</subject><subject>Hepacivirus - classification</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis C, Chronic - drug therapy</subject><subject>Hepatitis C, Chronic - virology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Oligonucleotides, Antisense - administration & dosage</subject><subject>Oligonucleotides, Antisense - metabolism</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Oligonucleotides, Antisense - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>RNA, Viral - genetics</subject><subject>RNA, Viral - metabolism</subject><subject>Sequence Analysis, DNA</subject><subject>Treatment Outcome</subject><subject>Viral Load</subject><issn>1359-6535</issn><issn>2040-2058</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNplkl1rFDEUhkdR7Fr9A15obpQWOpqPyXxcylLtQkFwtbdDJnPSjcwk2yQj-u89sQNFhEBykud93ySconjF6HvGmuYDE7KrpZC0orSjtGb8cbHhWJWcyvZJsclAmYmT4nmMPyjlLXLPihMma8kaWW0evbmxwU_-1mo1ETAGdIrEG7Lb7_aEVS0VF0Q5HMlGcBGIn-ytd4uewCc7ArHuYAebfMiqAxxVsoiSLflpwxLJ2dX25hyhBMFhQrCDj34GAi6F3yTaBORs9_Vyf35BvCMIk1yhgOhD8M7qfzzzCpUR7zMS-KVm63AHhZidDkCOPuGxzUF-grx7DHZWmJQFEbR3Y65yToBoY1JO5zf8Vfsl6Xy3bBZApRm9XhRPjZoivFzn0-L7p8tv26vy-svn3fbjdal5R3kJkjEuaDW0ujKqpmOn2wZqoJxTQceay3YQIA2tjRZG8rpqJGsbrVjHTSeFOC3e3fseg79bIKZ-tlHDNCkHfol93XDWtQ1HkN-DOvgYA5h-fWLPaJ_bov-_LVD0enVfhhnGB8naBwi8XQEVsRNMwH-x8YGrRScEr8QfdnnBEw</recordid><startdate>200412</startdate><enddate>200412</enddate><creator>SOLER, Muriel</creator><creator>MCHUTCHISON, John G</creator><creator>KWOH, T. 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Drug treatments</topic><topic>RNA, Viral - genetics</topic><topic>RNA, Viral - metabolism</topic><topic>Sequence Analysis, DNA</topic><topic>Treatment Outcome</topic><topic>Viral Load</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SOLER, Muriel</creatorcontrib><creatorcontrib>MCHUTCHISON, John G</creatorcontrib><creatorcontrib>KWOH, T. Jesse</creatorcontrib><creatorcontrib>DORR, F. 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Andrew</au><au>PAWLOTSKY, Jean-Michel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination of the potential role of primary and secondary HCV resistance in the outcome of treatment</atitle><jtitle>Antiviral therapy</jtitle><addtitle>Antivir Ther</addtitle><date>2004-12</date><risdate>2004</risdate><volume>9</volume><issue>6</issue><spage>953</spage><epage>968</epage><pages>953-968</pages><issn>1359-6535</issn><eissn>2040-2058</eissn><abstract>Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.</abstract><cop>London</cop><pub>International Medical Press</pub><pmid>15651754</pmid><doi>10.1177/135965350400900612</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Antiviral therapy, 2004-12, Vol.9 (6), p.953-968 |
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| source | SAGE Open Access |
| subjects | 5' Untranslated Regions - genetics Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Base Sequence Biological and medical sciences Drug Resistance, Viral Evolution, Molecular Hepacivirus - classification Hepacivirus - drug effects Hepacivirus - genetics Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - virology Humans Medical sciences Molecular Sequence Data Oligonucleotides, Antisense - administration & dosage Oligonucleotides, Antisense - metabolism Oligonucleotides, Antisense - pharmacology Oligonucleotides, Antisense - therapeutic use Pharmacology. Drug treatments RNA, Viral - genetics RNA, Viral - metabolism Sequence Analysis, DNA Treatment Outcome Viral Load |
| title | Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination of the potential role of primary and secondary HCV resistance in the outcome of treatment |
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